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Lin Xia, Zhongqiu Wang, Ying Zhang, Xiao Yang, Yibei Zhan, Rui Cheng, Shiming Wang and Jianfa Zhang

A previous investigation has demonstrated that plasma 5′-AMP (pAMP) exacerbates and causes hyperglycemia in diabetic mice. However, the crosstalk between pAMP and insulin signaling to regulate glucose homeostasis has not been investigated in depth. In this study, we showed that the blood glucose level was more dependent on the ratio of insulin to pAMP than on the absolute level of these two factors. Administration of 5′-AMP significantly attenuated the insulin-stimulated insulin receptor (IR) autophosphorylation in the liver and muscle tissues, resulting in the inhibition of downstream AKT phosphorylation. A docking analysis indicated that adenosine was a potential inhibitor of IR tyrosine kinase. Moreover, the 5′-AMP treatment elevated the ATP level in the pancreas and in the isolated islets, stimulating insulin secretion and increasing the plasma level of insulin. The insulin administration decreased the 5′-AMP-induced hyper-adenosine level by the up-regulation of adenosine kinase activities. Our results indicate that blood glucose homeostasis is reciprocally regulated by pAMP and insulin.

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Xiaojun Zhou, Jianjun Dong, Li Zhang, Ju Liu, Xiaofeng Dong, Qing Yang, Fupeng Liu and Lin Liao

It is well known that hyperglycemia is a trigger of atherosclerosis in patients with diabetes mellitus. However, the role of hyperglycemia in restenosis remains unclear. In this study, we investigated the effects of hyperglycemia on restenosis. Stenosis was evaluated in two sets of diabetic rabbit models: i) diabetic restenosis versus nondiabetic restenosis and ii) diabetic atherosclerosis versus nondiabetic atherosclerosis. Our results indicated that there was no difference in rates of stenosis between the diabetic and the nondiabetic groups in restenosis rabbit models. However, the incidence of stenosis was significantly higher in the diabetic atherosclerosis group compared with the nondiabetic atherosclerosis group. Similarly, the intima–media thickness and cell proliferation rate were significantly increased in the diabetic atherosclerosis group compared with the nondiabetic atherosclerosis group, but there was no difference between the diabetic restenosis and the nondiabetic restenosis groups. Our results indicate that hyperglycemia is an independent risk factor for atherosclerosis, but it has no evident effect on restenosis. These findings indicate that the processes of atherosclerosis and restenosis may involve different pathological mechanisms.

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Jiannan Zhang, Xin Li, Yawei Zhou, Lin Cui, Jing Li, Chenlei Wu, Yiping Wan, Juan Li and Yajun Wang

The interaction of melanocortin-4 (MC4R) and melanocortin-3 (MC3R) receptors with proopiomelanocortin (POMC)-derived peptides (e.g. α-MSH), agouti-related protein (AgRP) and melanocortin-2 receptor accessory protein 2 (MRAP2) is suggested to play critical roles in energy balance of vertebrates. However, evidence on their interaction in birds remains scarce. Our study aims to reveal their interaction in chickens and the results showed that (1) chicken (c-)MC3R and cMC4R expressed in Chinese hamster ovary (CHO) cells can be activated by α-MSH and ACTH1–39 equipotently, monitored by a pGL3-CRE-luciferase reporter system; (2) cMC3R and cMC4R, when co-expressed with cMRAP2 (or cMRAP, a cMRAP2 homolog), show increased sensitivity to ACTH treatment and thus likely act as ACTH-preferring receptors, and the interaction between cMC3R/cMC4R and cMRAP2 was demonstrated by co-immunoprecipitation assay; (3) both cMC3R and cMC4R display constitutive activity when expressed in CHO cells, as monitored by dual-luciferase reporter assay, and cMRAP2 (and cMRAP) can modulate their constitutive activity; (4) AgRP inhibits the constitutive activity of cMC3R/cMC4R, and it also antagonizes ACTH/α-MSH action on cMC4R/cMC3R, indicating that AgRP functions as the inverse agonist and antagonist for both receptors. These findings, together with the co-expression of cMC4R, cMC3R, cMRAP2, cAgRP and cPOMC in chicken hypothalamus detected by quantitative real-time PCR, suggest that within the hypothalamus, α-MSH/ACTH, AgRP and MRAP2 may interact at the MC4R(/MC3R) interface to control energy balance. Furthermore, our data provide novel proof for the involvement of MRAP2 (and MRAP) in fine-tuning the constitutive activity and ligand sensitivity and selectivity of both MC3R and MC4R in vertebrates.

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Chun Zeng, Xin Yi, Danny Zipris, Hongli Liu, Lin Zhang, Qiaoyun Zheng, Krishnamurthy Malathi, Ge Jin and Aimin Zhou

The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.

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Xigui Huang, Baowei Jiao, Chun Kit Fung, Yong Zhang, Walter K K Ho, Chi Bun Chan, Haoran Lin, Deshou Wang and Christopher H K Cheng

Two prolactin receptors (PRLRs) encoded by two different genes were identified in the fugu and zebrafish genomes but not in the genomes of other vertebrates. Subsequently, two cDNA sequences corresponding to two PRLRs were identified in black seabream and Nile tilapia. Phylogenetic analysis of PRLR sequences in various vertebrates indicated that the coexistence of two PRLRs in a single species is a unique phenomenon in teleosts. Both PRLRs in teleosts (the classical one named as PRLR1, the newly identified one as PRLR2) resemble the long-form mammalian PRLRs. However, despite their overall structural similarities, the two PRLR subtypes in fish share very low amino acid similarities (about 30%), mainly due to differences in the intracellular domain. In particular, the Box 2 region and some intracellular tyrosine residues are missing in PRLR2. Tissue distribution study by real-time PCR in black seabream (sb) revealed that both receptors (sbPRLR1 and sbPRLR2) are widely expressed in different tissues. In gill, the expression level of sbPRLR2 is much higher than that of sbPRLR1. In the intestine, the expression of sbPRLR1 is higher than that of sbPRLR2. The expression levels of both receptors are relatively low in most other tissues, with sbPRLR1 generally higher than sbPRLR2. The sbPRLR1 and sbPRLR2 were functionally expressed in cultured human embryonic kidney 293 cells. Both receptors can activate the β-casein and c-fos promoters; however, only sbPRLR1 but not sbPRLR2 can activate the Spi promoter upon receptor stimulation in a ligand-specific manner. These results indicate that both receptors share some common functions but are distinctly different from each other in mobilizing post-receptor events. When challenged with different steroid hormones, the two PRLRs exhibited very different gene expression patterns in the seabream kidney. The sbPRLR1 expression was up-regulated by estradiol and cortisol, whereas testosterone had no significant effect. For sbPRLR2, its expression was down-regulated by estradiol and testosterone, while cortisol exerted no significant effect. The 5′-flanking regions of the sbPRLR1 and sbPRLR2 genes were cloned and the promoter activities were studied in transfected GAKS cells in the absence or presence of different steroid hormones. The results of the promoter studies were in general agreement with the in vivo hormonal regulation of gene expression results. The sbPRLR1 gene promoter activity was activated by estradiol and cortisol, but not by testosterone. In contrast, the sbPRLR2 gene promoter activity was inhibited by estradiol, cortisol, and testosterone.

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Quan Wu, Ying Zhou, Linfeng Chen, Jiandang Shi, Chun-Yu Wang, Lin Miao, Helmut Klocker, Irwin Park, Chung Lee and Ju Zhang

Estradiol (E2) level in stroma of benign prostatic hyperplasia (BPH) increases with age, and this increase was associated with an elevated expression of aromatase in prostatic stromal cells (PrSCs). Here, we showed that conditioned medium (CM) of BPH-1 (a benign hyperplastic prostatic epithelial cell line), but not of prostate cancer cell lines (LNCaP, DU-145, and PC-3), stimulates aromatase expression in PrSCs. Cyclooxygenase-2 (COX-2) mRNA level in BPH-1, as well as prostaglandin E2 (PGE2) concentration in BPH-1 CM, was significantly higher than that of prostate cancer cell lines. CM of BPH-1 treated with NS-398 (a specific inhibitor of COX-2) failed to stimulate aromatase expression in PrSCs. And PGE2 can stimulate aromatase expression in PrSCs. Our data suggested that BPH-1 induced aromatase expression in PrSCs through the production of PGE2 in a paracrine mechanism.

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Shuisheng Li, Yong Zhang, Yun Liu, Xigui Huang, Weiren Huang, Danqi Lu, Pei Zhu, Yu Shi, Christopher H K Cheng, Xiaochun Liu and Haoran Lin

To ascertain the neuroendocrine function of the kisspeptin/GPR54 system in non-mammalian species, full-length cDNAs encoding for Kiss1 and Kiss2 as well as their putative cognate receptors GPR54a and GPR54b, were isolated from goldfish (Carassius auratus). The deduced protein sequences between Kiss1 and Kiss2 in goldfish share very low similarity, but their putative mature peptides (kisspeptin-10) are relatively conserved. RT-PCR analysis demonstrated that the goldfish kiss1 gene (gfkiss1) is highly expressed in the optic tectum-thalamus, intestine, kidney, and testis, while the goldfish kiss2 gene (gfkiss2) is mainly detected in the hypothalamus, telencephalon, optic tectum thalamus, adipose tissue, kidney, heart, and gonads. The two receptor genes (gfgpr54a and gfgpr54b) are highly expressed in the brain regions including telencephalon, optic tectum thalamus, and hypothalamus. Both mature goldfish kisspeptin-10 peptides (gfKiss1–10 and gfKiss2–10) are biologically active as they could functionally interact with the two goldfish receptors expressed in cultured eukaryotic cells to trigger the downstream signaling pathways with different potencies. The actions of gfKiss1–10 and gfKiss2–10 on LH secretion were further investigated in vitro and in vivo. Intraperitoneal administration of gfKiss1–10 to sexually mature female goldfish could increase the serum LH levels. However, this peptide does not significantly influence LH release from goldfish pituitary cells in primary culture, indicating that the peptide does not exert its actions at the pituitary level. On the other hand, gfKiss2–10 appears to be a much less potent peptide as it exhibits no significant in vivo bioactivity and is also inactive on the primary pituitary cells.

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Yong Zhang, Yun Liu, Xigui Huang, Xiaochun Liu, Baowei Jiao, Zining Meng, Pei Zhu, Shuisheng Li, Haoran Lin and Christopher H K Cheng

Two GPR39 transcripts, designated as sbGPR39-1a and sbGPR39-1b, were identified in black seabream (Acanthopagrus schlegeli). The deduced amino acid (aa) sequence of sbGPR39-1a contains 423 residues with seven putative transmembrane (TM) domains. On the other hand, sbGPR39-1b contains 284 aa residues with only five putative TM domains. Northern blot analysis confirmed the presence of two GPR39 transcripts in the seabream intestine, stomach, and liver. Apart from seabream, the presence of two GPR39 transcripts was also found to exist in a number of teleosts (zebrafish and pufferfish) and mammals (human and mouse). Analysis of the GPR39 gene structure in different species suggests that the two GPR39 transcripts are generated by alternative splicing. When the seabream receptors were expressed in cultured HEK293 cells, Zn2 + could trigger sbGPR39-1a signaling through the serum response element pathway, but no such functionality could be detected for the sbGPR39-1b receptor. The two receptors were found to be differentially expressed in seabream tissues. sbGPR39-1a is predominantly expressed in the gastrointestinal tract. On the other hand, sbGPR39-1b is widely expressed in most central and peripheral tissues except muscle and ovary. The expression of sbGPR39-1a in the intestine and the expression of sbGPR39-1b in the hypothalamus were decreased significantly during food deprivation in seabream. On the contrary, the expression of the GH secretagogue receptors (sbGHSR-1a and sbGHSR-1b) was significantly increased in the hypothalamus of the food-deprived seabream. The reciprocal regulatory patterns of expression of these two genes suggest that both of them are involved in controlling the physiological response of the organism during starvation.

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You-Hua Xu, Chen-Lin Gao, Heng-Li Guo, Wen-Qian Zhang, Wei Huang, Shan-Shan Tang, Wen-Jun Gan, Yong Xu, Hua Zhou and Quan Zhu

Endotoxemia has been recognized to be closely accompanied with type 2 diabetes mellitus (T2DM) and is responsible for many diabetic complications. Recent study suggests the potential role of butyrate, a short-chain fatty acid (SCFA) from microbiota metabolite, on T2DM. Gut-leak is a key event in diabetic-endotoxemia. To investigate if butyrate could ameliorate diabetic-endotoxemia, both in vivo and in vitro experiments were carried out in the present study. The effect of butyrate supplementation on blood HbA1c and inflammatory cytokines were determined in db/db mice; gut barrier integrity and expression of tight junction proteins were investigated both in vivo and in vitro. Oral butyrate administration significantly decreased blood HbA1c, inflammatory cytokines and LPS in db/db mice; inflammatory cell infiltration was reduced, and gut integrity and intercellular adhesion molecules were increased as detected by HE staining, immunohistochemistry and Western blot. By gut microbiota assay, ratio of Firmicutes:Bacteroidetes for gut microbiota was reduced by butyrate. In Caco-2 cells, butyrate significantly promoted cell proliferation, decreased inflammatory cytokines’ secretion, enhanced cell anti-oxidative stress ability and preserved the epithelial monocellular integrity, which was damaged by LPS. The present findings demonstrated that butyrate supplementation could ameliorate diabetic-endotoxemia in db/db mice via restoring composition of gut microbiota and preserving gut epithelial barrier integrity.

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B T Layden, V Durai, M V Newman, A M Marinelarena, C W Ahn, G Feng, S Lin, X Zhang, D B Kaufman, N Jafari, G L Sørensen and W L Lowe Jr

Pancreatic β cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in β cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased β cell proliferation (E13.5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine-induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using real-time reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13.5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy.